Alpha - cyclopropylethf



UNITED" STATES PATENT OFFICE ALPHA CYCLOPROPYLETHYL SUBS'IL TUTED BARBLTUBIC ACIDS AND PROCESS FOR. PREPARING SAME Joseph W. 0pie,-Minneapolis, Minn., and Joseph Seifter, Willow Grove, William F. Bruce; Havertown, and George Mueller, Philadelphia; Pin,v assignors to Wyeth Incorporated, Philadelphia Pat, a-c'orporation. of Belaware No Drawing. Application December 21, 1946, Serial N0. 717,806

Claims; 1 This invention relates to new barbituric and thiobarbiturie acid derivatives and methods for preparing them; More particularly, the invention relatestomethods" for preparing barbituric and thiobarbituric acid derivative havingan alpha-cyclopropylethyl radical and an alkyl, alicyclic, alicyclicalkyl or alke'nyl radical attached to the 5-carb'on atom of the barbituric or thiobarbituric ring; and to'specific barbituric and thiobarbiturio compounds.

The compounds made" in accordance with the disclosed methods may be represented by the Structural formula:

cm. on,

COMNQRI' i -=2:- to-N4 where R is an alkyl radical of 2 to 5 carbon atoms, an alicyclic radical of 3 to 5 carbon atoms, an alicyclicallcyl radical of. 4 to 5 carbon atoms, or

an alkenyl radical having 3 to 5 carbon:v atoms,

R1 is H or an alkyl radical of 1 to 2 carbon atoms, X represents 0 or Sand Y represents a member of the group consisting of hydrogen, an alkali metal, an alkaline earth metal,- ammonium, or in fact, any salt of an organic base such as alkyl ammonium or dialkyl ammonium.

cyclopropyl barbiturates falling" within the scope of the invention are usefulpharmacolo n cally as anesthetics, sedatives, ariticonvulsants, soporificsand hypnotics, displaying a relatively fast action of comparative short duration which properties render the new compounds suitable for specific' therapeutic purposes.

In accordance" with thepresent invention. the new bai'bituricor thiob'arbituric acids are obtainable by condensing methyl cyclopropyl ketone with cyanoacetamide, malononitrile 'or ethyl cya'noacetate to form a mixture of cis and trans forms of the alpha cyclopropyl ethylidenecyanoacetamide, -malononitrile or -ethyloyanoacetate. The condensation product is reduced with hydrogen and a catalyst to form a mix-- alicyclic, alicyclicalk'yl or alk'enyl halide to form the corresponding alkylated compound which is then condensed with urea, guanidine, thiourea or the mono-N-allwlate'd derivatives of these, or, in the case of the alkylated alpha-cyclopropyl ethylcyanoacetamide or the ethylmalononi'trile', these compounds may first be hydrolyzed and then esterified prior to the condensationstep. Inany case, the condensation product is finally hydrolyzed. to form the S-alpha-cyclopropylethy1-5-a1kyl, alicyclic, -a1icyc1ica1ky1 or- -alkenyl barbituric or thiobarbituric acid deriviatives. I

The invention is further illustrated by the following examples.

EXAMPLE-I Preparation of alpha-cyclopropylethylidene ethyl cyanoacetate To a mixture of 1130s. oi etl'iylcyanoacetate, 840 g. of methylcyclopropyl ketonean'd 1000- cc; of benzene, there was added 77 g. of ammonium acetate (moist) and 120 g. of glacial acetic acid. The mixture was refluxed vfor 32 hours,' or until no more water distilled. over with the benzene, the water layer being" removed from a water separator. The total waterremoved was 201 cc. After completion of the reaction approximately 300 cc. of ether was added and the solution washed twice with 100 g. of sodium chloride in 1600 cc. of water. Thebenzehe layer was -se'parated; filtered through sodium sulfate, and the benzene distilled olT in vacuo. The product was 3 giving a mixture of the crystalline and liquid isomers. The total yield of the two geometric isomers of 'alpha-cyclopropylethylidene ethylcyanoacetate was 1449 g. (81%). The crystalline isomer may be recrystallized from ethyl alcohol. The pure crystals had a melting point of 81-82 C.

ANALYSIS Calcd for C1oH1aNO2: C, 67.03 H, 7.26 N, 7.82

Found: C, 66.99 H, 7.34 N, 7.79

EXAMPLE II Condensation of methylcyclopropyl ketone with cyanoacetamide A mixture of 168 g. (2 moles) methyl cyclopropyl ketone, 168 g. (2 moles) cyanoacetamide, 15.4 g. moist ammonium acetate, 24 cc. glacial acetic acid and 200 cc. of benzene was refluxed for 6 hours using a water separator. At this time 37.5 cc. of water was collected. The hot benzene solution was poured into a crystallizing dish and allowed to come to room temperature; the crystalline solid which formed was filtered oil, washed with benzene and water and was air dried. The product melted at 98-100 and weighed 221 g. or 73.5 g. or 73.5%. A 10 g. portion was recrystallized from hot water and treated with carbon yielding material melting at- 116-124". Recrystallization from hot ethanol gave material melting at 166-167. Further recrystallization from benzene did not raise the melting point.

ANALYSIS Calcd for CsHmNzO: C, 64.00 H,- 6.66 N, 18.66 Found: C, 64.20 H, 7.08 N, 18.89

EXAMPLE III methylcyclopropyl ketone with malononitrile Malononitrile, 76 g. (1.15 moles), methylcyclopropyl ketone, 109 g. (1.3 moles), 8 g. of wet ammom'um acetate crystals, 12 cc. of glacial acetic acid and100 cc. of benzene-were heated during 4.5,:hoursg. 29, cc. lofxaque'ousz phase collected in a water collector attached beneath the reflux condenser. "The cooled mixture was .diluted with an equal volume of ether, washed-:4: times with an equal volume of water each time and concentrated in vacuo. The yield of crude concentrate was 100%. The material was distilled, B. P. 135-137/6 'mm-.;- yield 141 g. (93%); The product was a solid crystallizing in the receiver. When recrystallized-from aqueous methanol or ethanol elongated colorless plates, M. P. 65.5- 66.6", were obtained.

I 4 AN LrsIs Calcd'for CsHaN2:' ,,C,"72.70"H, 6.10 N, 21.20

Condensation of Found: (1, 72.81 H,'5.98 N, 21.44

' EXAMPLE IV Preparation of alpha cyclopropylethyl-cyanoacetic acid ethyl ester of hydrogen. The catalyst was filtered off. The

alcohol was removed in vacuo-, and the residue was vacuum distilled. The product boiled at ANALYSIS Calcd fol; CioHisNOz: C, 66.29 H, 8.28 N, 7.73 Found: C, 66.32 H, 8.29 N, 7.47

In place ofthe palladium on charcoal catalyst, Raney nickel catalyst activated with one quarter of its weight of 5% palladium 'on" charcoal may beused as the hydrogenation catalyst.

EXAMPLE V Preparation #1 of alpha-(alpha-cyclopropylethyl) -alpha-et]tyl cyanoacetic acid ethyl ester The hydrogenated cyano ester prepared in accordance with Example IV (46 g., 0.25 m.) was added to a cold solution of sodium (6 g.) in absolute isopropanol (200 cc.). The mixture was stirred for a few minutes during which period it became dark orange in color. Diethyl-sulfate (39 g.; 0.25 m.) was added all at one time and the solution was heated'to boiling. An exothermic reaction took place lasting for about30 minutes during which time external heating was discontinued. At the end of this period, the orange color had disappeared and the solution was-hen; tral to moist indicator paper. A heavy precipitate of sodium sulfate was suspended in theselution at this point. The mixture was poured over ice, and the aqueous suspension was extracted with 3x200 cc. of benzene. The benzene extract was washed with water, filtered, dried over sodium sulfate, filtered again and then concentrated in vacuo. The residue which remained when all of the benzene had been re- 1 moved was vacuum distilled. The material boil- Calcd for C12Hi9NOz: c, 68.86 H, 9.15.-N, 6.69 Found: 0, 68.66 H, 9.22 N, 6.72

EXAMPLE v1 Preparation #2 of alpha-(alpha-cyclopropylethyl) -alpha-ethyl cyanoacetic acid ethylester Y Clean sodium metal (0.535 mole) was dissolved in 200 cc. of absolute alcohol. Most of the alcohol was removed in vacuo from this solution and a solution of 0.535 mole of ethyl-alpha cyclopro pylethyl-cyanoacetate in 300 g. of'diethyl carbonate was added. All the alcohol was distilled from this solution while heating and stirring.- Ethyl bromide, 0.65 mole, was added, the-mixture heated one hour, then 10 g. more of ethyl bro-- mide added and heating continued 45 hours. After standing 21 hours, the mixture was worked up with water and ether. It was not acid to phenolphthalein. The solvents were removed and the product distilled. Thev product was collected between 95.l-98.2- C. at- 2.9 mm.; 11 16406.. A I

5;. I EXAMPLE VII Preparation #3 of alpha-(alpha-cyclopropylethyl) -aZpha'-ethyl cyanoacetic acid ethyl ester Clean sodium metal (0.50 moles) was added to 300 cc. of absolute ethanol; just before dissolution was complete and while the solution wasat 60, 105 g. (0.58 mole) of ethyl-alpha-cyclopropylethyl-cyanoacetate was introduced quickly and within five minutes of completing this addition, 71 g. (0.65 mole) of ethyl bromide was added rapidly, Within five minutes, sodium bromiderbegan to precipitate and the temperature rose to reflux temperature where it remained during an hour.

External heating was then applied and the mix ture heated at slow reflux with stirring for 23 hours, after which 180 cc. of alcohol was distilled off. The cooled mixture was then poured into Water and extracted with ether, the ether extract dried and distilled. The product was collected between 95.1-09.0 C. at 2.9 mm.; n 1.4445.

EXAMPLE VIII Preparation #4 of alpha-(alpha-cyclopropylethyl) -aZpha'-ethyl cyanoacetic. acid ethyl ester anadditional amount. of 10;.g. of ethyl bromide was added and heating continued for 4 hours. The cooled solution was worked up with. water and ether, and. the ethereal solution dried and distilled in vacuo. The product was collected between 96.0-98.0 C. at 2.9 mrm; n 1.4413.

. While these examples illustrate the preparation 'of the ethyl derivative, the corresponding alicyclic or alicyclicalkyl derivatives may be prepared in the same way using the corresponding halide in place of ethyl bromide, In the same way, the corresponding. alkenyl derivative may be prepared by using an alkenyl halide, as for example, allyl bromide in place of ethyl bromide.

EXAMPLE IX Preparation fi alpha-cyclopropylethyl--ethyl barbituric acid Sodium (16.7 gt, 0.725 m.) was dissolved-in a1"- cohol (250cc); Urea ('2l.7'5'g.,'0.36'm.) was added to this hotsolution, and the alkylation product ('66.'7'g., 0.29 m.) was then added. The mixture was refluxed at 530-100 C. for'48 hours. The alcohol was distilled from this solution under vacuum, and the residue was dissolved in 200 cc. of water. This solution was extracted twice with ether, which was discarded. The aqueous solution was made acid and then diluted with an equivalent volume of concentrated hydrochloric acid. This solution was refluxed for fourteen hours. It was then chilled and extracted with ether. The ether was evaporated, and the residue was dissolved in sodium hydroxide. This solution was boiled with charcoal, filtered and acidified. The solution was extracted with ether. The ether was evaporated, and the residue was dissolved in absolute ether. The barbituric acid derivative was precipitated from this solution with. petroleum ether. The product melted at l49-152 C. Upon crystallization from etherpetroleum ether,.itmeltedat162463 C.

ill

ANALY SI S "Calc'd ror 'ounlemoaz c, 58.92 H, "1.14 N, 12.50

Found: C, 59.06 H, 7.20 N, 12.65

While urea has been used in the above condensation, similar results may be obtained using EXAMPLE X Preparation of the salts of barbituric and thiobarbituric acid The salts of the'new barbituric and thiobarbituric acid derivatives are obtained by neutralizing With bases in the well-known manner, as for example with alkali metal hydroxide or alcoholate, alkaline earth metal hydroxide or alcoholate, an

aqueous or alcoholic solution of concentrated ammonia or with an alkyl amine such as methyl or ethyl amine or with a dialkyl amine such asdimethyl or diethylamine. The following procedures illustrate the formation of typical watersoluble salts- I 7 Sodium salt: To the solid, water-insoluble 5- alpha-cyclopropylethyl-5-ethyl barbituric acid, 0.0223 g. (0.000 1 mole), the addition of 0.4 cc. of a solution containing 0.00025 mole/cc. of sodium hydroxide in ethanol gave a clear solution of the sodium barbiturate. Addition of 10-15 cc. of anhydrous ether precipitated the salt which was separated by centrifuging, washed with anhydrous ether, separated and dried. The salt was water-soluble.

Magnesium salt: Ihe solid barbiturate, 0.1115 g. (0.0005 mole) readily dissolved inl.0 cc. of methanol containing 0.0005 mole/cc. of magnesium. The saltwas precipitated and washed with dry ether as in the preparation of the sodiumsalt. The. addition of 0.00025 mole of an alkaline. earth metal methylate to 0.0005 mole of the barbiturate precipitated only the equivalent of an alkaline earth metal salt -(hydroxyalkaline earth metal salt) which was also water-soluble.

In the same way, one molar proportion of any of the above-described 5,5-disubstituted barbituric or thiobarbituric acid derivatives is added to about one molar proportion of an aqueous or alcoholic solution of concentrated ammonia or an alkyl or dialkyl amine. The resulting salt is separated, washed and dried.

The new compounds display marked pharmacological action. Tables I and II disclose comparative tests carried out on iniceand rabbits using 5-alpha-cyc1opropylethyl-5-ethyl barbi turic acid compared to various well-known barbituric acid compounds. In carrying out these tests, Table I illustrates determinations on mice while Table II illustrates determinations by intravenous injection on rabbits. The term LDso is defined as the dosage, required to kill 50% of the animals, determined by intraperitoneal TABLE I Comparative action of various barbiturates in mice Average Average Sodium 5,5-Disubstituted LDm in MHDm in Onset at Duration Barbituratc mg./kg. mg./kg. MHDm m at MHDw min. in min.

1. Diethyl e11 135 52 91 2. Phenyl-ethyl 199.6 86 52 187 3. Ethyl-isopropyl. 58 39 129 4. Ethyl-(lmethy1-l-but yl 53 20 21 5. Allyl-isopropyl 37 38 58 6. Ethyl-l-mcthylbutyl... 28 12 25 7. Allyl-l'methylbuty 36 34 8. Ethyl-alpha-oyclopropylethyl 138.5 24 12 27 The data in Table I indicates that the tested compound of the invention when compared with other well-known barbiturates is well tolerated and relatively non-toxic, disclosing a relatively fast action for a short duration and is effective in relatively small dosage.

TABLE II Comparative action of various barbiturates in rabbits I Average Average Sodium 5,5-Disubstituted Bar- MHD, Onset at Duration bituratc nag/kg. MHD, at MHD,

min. min.

1. Dieth 110 43 133 2. Phenyl-ethyL... 70 19 131 3. Ethyl-isopropyl 40 16 2% 4. Ethyl-(l-1netl1yl-l-bntenyl) 11 2t 5. Allyi-isopropyl 28 13 3') 6. Ethyl-l-mcthylbut 15 6 d2 7. Allyl-l-metnylouty 13 2 19 8. Ethyl-alplia-cyclopropylothyl. 18 8 79 in which R represents a member selected from the group consisting of an alkyl radical of 2 to 5 carbon atoms, an alicyclic radical of 3 to 5 carbon atoms, and an alicyclicalkyl radical of 4 to 5 carbon atoms; R1 represents a member selected from the group consisting of hydrogen and an alkyl of 1 to 2 carbon atoms; X represents a member selected from the group consisting of O and S; and Y represents a member selected from the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonim, alkylammonium and dialkylammonium.

2. A barbituric compound represented by the formula:

in which R represents a member selected from the group consisting of an alkyl radical of 2 to 5 carbon atoms, an alicyclic radical of 3 to 5 carbon atoms, and an alicyclicalkyl radical of 4 to 5 carbon atoms; R1 represents a member selected from the group consisting of hydrogen and an alkyl of 1 to 2 carbon atoms and Y represents a member selected from the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

3. A barbituric compound represented by the formula:

in which R represents a member selected from the group consisting of an alkyl radical of 2 to 5 carbon atoms, an alicyclic radical of 3 to 5 carbon atoms, and an alicyclicalkyl radical of 4 to 5 carbon atoms; R1 represents a member selected from the group consisting of hydrogen and an alkyl of 1 to 2 carbon atoms and Y represents a member selected from the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

4. A barbituric compound represented by the formula:

in which the representation alkyl in the formula stands for an alkyl radical having 2 to 5 carbon atoms, and in which X represents a member selected from the group consisting of O and S; and Y represents a member selected from the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

5. A barbituric compound represented by the formula:

in which R is a member selected from the group consisting of an alkyl radical of 2 to 5 carbon atoms, an alicyclic radical of 3 to 5 carbon atoms, and an alicyclicalkyl radical of 4 to 5 carbon atoms; Y represents a member selected from the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

9 v 6. A barbituric compound represented by the formula:

in which the representation alkyl in the formula stands for an alkyl radical having 2 to 5 carbon atoms, and in which Y represents a member selected from the group consisting of hydrogen, an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

7. A barbituric compound represented by formula:

the

in which R1 represents a member selected from the group consisting of hydrogen and an alkyl having 1 to 2 carbon atoms X represents a member selected from the group consisting of O and S; and Y represents a member selected from the group consisting of hydrogen an alkali metal, an alkaline earth metal, ammonium, alkylammonium and dialkylammonium.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,019,936 Shonle Nov. 5, 1935 2,150,154 Cope Mar. 14, 1939 2,176,018 Cope Oct. 10, 1939 OTHER REFERENCES Chemical Abstracts 32, 2912 (1938) 

1. A BARBITURIC COMPOUND REPRESENTED BY TH FOLLOWING FORMULA 